MYBPC3 in Hypertrophic Cardiomyopathy (HCM)

The role of rare variants in MYBPC3 as causative mutations in Hypertrophic Cardiomyopathy is described below. By comparing the frequency of MYBPC3 variants in large HCM clinical cohorts to the background population rate in the ExAC database, the proportion of HCM patients with pathogenic mutations in MYBPC3 can be estimated, as well as the likelihood that a rare (population allele frequency <0.0001) MYBPC3 variant identified in a HCM patient is disease-causing. Summary data for different variant classes (all protein-altering variants, loss of function truncating variants and non-truncating variants) is highlighted - see the table below for full details of this analysis.

Excess of MYBPC3 variants in HCM: 17.06% (p<0.0001)

Based on an analysis of all rare protein-altering variants (MAF<0.0001 in ExAC) in MYBPC3 found in 6179 HCM samples sequenced by OMGL and LMM and in reference samples of the ExAC population database.

Metrics by Variant Class:
All VarsTruncatingNon-Truncating
Excess in HCM 17.06%
Etiological fraction 0.91
0.91 - 0.92
0.99 - 0.99
0.80 - 0.84
Odds Ratio 11.70
10.67 - 12.82
86.00 - 168.20
5.12 - 6.35

The Etiological Fraction (EF) is the proportion of affected carriers where the variant caused HCM. The Odds Ratio (OR) describes the odds of having a rare variant in the patient cohort to the odds in the ExAC cohort. Fisher's exact test p-values are displayed for case excess, 95% confidence intervals for EFs and ORs.

in HCM
in ExAC
Case Excess
in HCM
(OMGL1 + LMM2)
6179All1176 0.190320.019700.17062
Truncating566 0.091600.000860.09074
Non-Truncating610 0.098720.018840.07988
OMGL13267All636 0.194670.019700.17497
Truncating298 0.091220.000860.09036
Non-Truncating338 0.103460.018840.08462
LMM22912All540 0.185440.019700.16574
Truncating268 0.092030.000860.09117
Non-Truncating272 0.093410.018840.07457


1. Roddy Walsh, Kate L. Thomson, James S. Ware, Birgit H. Funke, Jessica Woodley, Karen J. McGuire, Francesco Mazzarotto, Edward Blair, Anneke Seller, Jenny C. Taylor, Eric V. Minikel, Exome Aggregation Consortium, Daniel G. MacArthur, Martin Farrall, Stuart A. Cook and Hugh Watkins. Reassessment of Mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples. Genet Med. 2016 doi:10.1038/gim.2016.90.

2. Alfares AA, Kelly MA, McDermott G, Funke BH, Lebo MS, Baxter SB, Shen J, McLaughlin HM, Clark EH, Babb LJ, Cox SW, DePalma SR, Ho CY, Seidman JG, Seidman CE, Rehm HL. Results of clinical genetic testing of 2,912 probands with hypertrophic cardiomyopathy: expanded panels offer limited additional sensitivity. Genet Med. 2015 Nov;17(11):880-8.